TY - JOUR
T1 - The cutting edges in DNA repair, licensing, and fidelity
T2 - DNA and RNA repair nucleases sculpt DNA to measure twice, cut once
AU - Tsutakawa, Susan E.
AU - Lafrance-Vanasse, Julien
AU - Tainer, John A.
N1 - Funding Information:
Work for this review and the authors′ efforts were funded by NIH RO1CA081967 , RO1GM46312 , and P01CA092584 . J.L.V. is recipient of a fellowship from the Canadian Research Institutes of Health Research (CIHR) .
PY - 2014/7
Y1 - 2014/7
N2 - To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. Damage identification is a challenge for all DNA damage response proteins, but especially for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? Combined structural, biochemical, and biological analyses of repair nucleases are revealing their molecular tools for damage verification and safeguarding against inadvertent incision. Surprisingly, these enzymes also often act on RNA, which deserves more attention. Here, we review protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), UV Damage endonuclease (UVDE), very short patch repair endonuclease (Vsr), Endonuclease V (Nfi), Flap endonuclease 1 (FEN1), exonuclease 1 (Exo1), RNase T and Meiotic recombination 11 (Mre11). DNA and RNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Currently their structural biology is most fully illuminated for DNA repair, which is also essential to life. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by James Watson and Francis Crick, that is only now being illuminated though structural biology and mutational analyses. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the old carpenter adage: measure twice, cut once. Furthermore, to measure twice these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency.
AB - To avoid genome instability, DNA repair nucleases must precisely target the correct damaged substrate before they are licensed to incise. Damage identification is a challenge for all DNA damage response proteins, but especially for nucleases that cut the DNA and necessarily create a cleaved DNA repair intermediate, likely more toxic than the initial damage. How do these enzymes achieve exquisite specificity without specific sequence recognition or, in some cases, without a non-canonical DNA nucleotide? Combined structural, biochemical, and biological analyses of repair nucleases are revealing their molecular tools for damage verification and safeguarding against inadvertent incision. Surprisingly, these enzymes also often act on RNA, which deserves more attention. Here, we review protein-DNA structures for nucleases involved in replication, base excision repair, mismatch repair, double strand break repair (DSBR), and telomere maintenance: apurinic/apyrimidinic endonuclease 1 (APE1), Endonuclease IV (Nfo), tyrosyl DNA phosphodiesterase (TDP2), UV Damage endonuclease (UVDE), very short patch repair endonuclease (Vsr), Endonuclease V (Nfi), Flap endonuclease 1 (FEN1), exonuclease 1 (Exo1), RNase T and Meiotic recombination 11 (Mre11). DNA and RNA structure-sensing nucleases are essential to life with roles in DNA replication, repair, and transcription. Increasingly these enzymes are employed as advanced tools for synthetic biology and as targets for cancer prognosis and interventions. Currently their structural biology is most fully illuminated for DNA repair, which is also essential to life. How DNA repair enzymes maintain genome fidelity is one of the DNA double helix secrets missed by James Watson and Francis Crick, that is only now being illuminated though structural biology and mutational analyses. Structures reveal motifs for repair nucleases and mechanisms whereby these enzymes follow the old carpenter adage: measure twice, cut once. Furthermore, to measure twice these nucleases act as molecular level transformers that typically reshape the DNA and sometimes themselves to achieve extraordinary specificity and efficiency.
KW - APE1
KW - Base excision repair
KW - Crystallography
KW - DNA
KW - DNA repair
KW - DNase
KW - Double strand break repair
KW - EndoIV
KW - EndoV
KW - Endonucleases
KW - Enzyme-DNA complex
KW - Exo1
KW - Exonuclease
KW - FEN1
KW - Genome maintenance
KW - Magnesium
KW - Manganese
KW - Metals
KW - Mismatch repair
KW - Mre11
KW - Nfi
KW - Nfo
KW - Nucleases
KW - Nucleotide incision repair
KW - RNA
KW - RNase
KW - Structure-specific nuclease
KW - TDP2
KW - Telomere
KW - UVDE
KW - Vsr
KW - Zinc
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U2 - 10.1016/j.dnarep.2014.03.022
DO - 10.1016/j.dnarep.2014.03.022
M3 - Article
C2 - 24754999
AN - SCOPUS:84902119190
SN - 1568-7864
VL - 19
SP - 95
EP - 107
JO - DNA Repair
JF - DNA Repair
ER -